Infections and anti–tumor necrosis factor α therapy

Authors


Introduction

Tumor necrosis factor α (TNFα) is a cytokine that plays a critical role in the regulation of inflammatory processes, both idiopathic and infectious. In the case of infection, one of its key roles is to facilitate cell-to-cell communication in the control of invasive infection. As might be expected, there is increasing evidence that inhibition of TNFα is associated with the development of serious infectious diseases (1) and difficulty clearing infections once they develop (2). At the same time, this treatment strategy has resulted in disease control in certain inflammatory diseases including rheumatoid arthritis (RA), Crohn's disease, psoriatic arthritis, and juvenile rheumatoid arthritis. The spectrum of pathogens causing invasive disease in patients receiving TNFα blockade therapy ranges from common gram-positive and gram-negative bacteria to more opportunistic organisms such as Mycobacterium tuberculosis, Cryptococcus, and Aspergillus (Table 1). The extent of the infections ranges from localized to disseminated. It appears that not only is the incidence of certain infections increased with anti-TNFα therapy, but the ability to contain these infections is also impaired. This underscores the need to develop measures to reduce the risk of infectious complications associated with TNF blockade.

Table 1. Infectious agents associated with tumor necrosis factor α inhibition
Mycobacteria
 Mycobacterium avium-intracellulare (1)
 Mycobacterium tuberculosis (13)
Bacteria
 Streptococccus pneumoniae (2)
 Listeria monocytogenes (34)
Fungi
 Candida albicans (1)
 Pneumocystis jiroveci (1)
 Aspergillus fumigatus (14)
 Histoplasma capsulatum (41)
 Cryptococcus neoformans (44)
 Coccidioides immitis (52)

The purpose of this review is to delineate the role of TNFα in host defense against infection, define the effects of TNFα blockade in clinical sepsis trials and in animal models of infection, and, most importantly, describe the variety of infections that have been reported in patients receiving anti-TNFα therapy. Recommendations aimed at preventing infectious complications and treating established infections associated with anti-TNFα therapy will be proposed. In the absence of any established controlled clinical trials designed to investigate strategies to limit anti-TNFα–associated infections, it is necessary to propose guidelines based on case reports, case series, anecdotal experience, and expert opinion. For other groups of immunocompromised patients, the concept of the therapeutic prescription (3) has been advocated, and it has been shown to be effective in the arena of transplantation. The therapeutic prescription has 2 components: an immunomodulating effect to control the underlying condition and an antimicrobial program to make disease-modifying therapy safer. Formulation of such a program requires a clear understanding of the host defense defects that are produced and the observed clinical infections that have occurred.

Background

TNFα is a cytokine within the TNF superfamily which acts as a central mediator of inflammation and immune regulation. It is synthesized and secreted chiefly by macrophages in response to proinflammatory stimuli such as bacterial lipopolysaccharide. It is expressed as a transmembrane protein and is functional on the cell surface, or, if cleaved by a specific metalloproteinase, is released from the cell surface as a soluble homotrimer. TNFα binds to cell surface receptors, TNF receptor I (TNFRI), and TNFRII (4).

TNFα antagonists have been demonstrated, in placebo-controlled clinical trials, to be highly effective in the treatment of certain inflammatory diseases such as RA (5–9), psoriatic arthritis (10), juvenile rheumatoid arthritis (11), and Crohn's disease (12)—disorders in which TNFα may have a significant role in pathogenesis. As of January 2003, 3 TNFα antagonists, the monoclonal antibodies infliximab and adalimimab and the p75 TNF soluble receptor etanercept, have been approved by the Food and Drug Administration (FDA) for clinical use in the US.

In clinical trials of these agents, an increased rate of serious infections was generally not noted. It was not until infliximab and etanercept were approved for and used in clinical practice that reports of sepsis, as well as tuberculosis (TB) and infections with atypical mycobacteria and other organisms, were observed. In 2001 an FDA advisory committee reviewed toxicity issues related to TNF inhibitors, specifically, infections that included TB, endemic fungi such as Histoplasmacapsulatum and Coccidioidesimmitis, yeasts such as Cryptococcus neoformans and Candida species, Pneumocystis pneumonia, molds such as Aspergillus, and bacteria such as Listeria monocytogenes (1).

Role in host defense

The biologic effects of TNFα on immune cells are remarkably broad (Table 2). Since TNFα plays a major role in monocyte, neutrophil, B cell, and T cell function, as well as in facilitating necessary communication among these cells, it is not surprising that the neutralization of TNFα has led to infections associated with impairments in the function of these cells. The increased risk of TB (13) and, in particular, extrapulmonary TB is reminiscent of findings in patients with depressed cell-mediated immunity (e.g., acquired immunodeficiency syndrome). Invasive aspergillosis (14) associated with anti-TNFα therapy has been described and may correlate with neutrophil- and/or cell-mediated immune dysfunction. Uncontrolled pneumococcal necrotizing fasciitis (2) as a result of anti-TNFα therapy may relate to phagocytic dysfunction.

Table 2. Biologic effects of tumor necrosis factor α (TNFα) on immune cells*
  • *

    Adapted, with permission, from ref. 29.

Monocyte/macrophages
 Activate
 Autoinduce TNFα
 Chemotaxis and migration
 Inhibit differentiation
 Suppress proliferation
Polymorphonuclear cells
 Increase phagocytosis
 Increase production of superoxide
 Stimulate integrin response
Lymphocytes
 Induce T cell colony formation
 Induce superoxide in B cells
 Induce apoptosis in mature T cells
 Activate cytotoxic T cell invasiveness

TNFα inhibition and sepsis

TNFα, in conjunction with other proinflammatory cytokines (i.e., interleukin-1), is an important mediator of sepsis. After the introduction of bacteria or endotoxin into the systemic circulation in animal models, the concentration of TNFα increases, and the effects of administration of TNFα in humans reproduce the physiologic and chemical changes seen in severe sepsis (15). Furthermore, antibodies directed against TNFα have exhibited a protective role in animal models of sepsis (16–18).

These observations led to clinical trials of anti-TNFα therapy in sepsis. In a study of the efficacy of etanercept in 141 patients with septic shock, there were 10 deaths among 33 patients in the placebo group (30% mortality), 9 deaths among 30 patients receiving low-dose etanercept (0.15 mg/kg body weight) (30% mortality), 14 deaths among 29 patients receiving intermediate-dose etanercept (0.45 mg/kg body weight) (48% mortality), and 26 deaths among 49 patients receiving high-dose etanercept (1.5 mg/kg body weight) (53% mortality) (19). There were more gram-positive infectious causes of sepsis in the 3 etanercept groups compared with the placebo group, in addition to an increase in Pseudomonas aeruginosa infection in the group receiving 0.45 mg/kg of etanercept (P = 0.08). In 2 other trials using TNF monoclonal antibodies for the treatment of sepsis, there was no significant difference in all-cause mortality at 28 days in patients who received placebo as compared with those who received TNFα monoclonal antibody (20, 21). These clinical data represent prima facie evidence that despite the role of TNFα in the augmentation and pathogenesis of sepsis, neutralization of this cytokine does not lead to improved survival; in fact, in the case of higher-dose etanercept, an increase in mortality was noted.

Infections associated with TNFα blockade

Mycobacterium tuberculosis.

TNFα plays an important role in the host defense against M tuberculosis. Kaneko et al (22) created a TNFα-knockout mouse model and demonstrated that challenge with Mtuberculosis decreased the survival time of these mice from 50 days to 33 days. At necropsy, the mice had diffuse abscesses in the lungs, liver, spleen, and kidneys. Histopathologically, the TNFα-knockout mice exhibited numerous necrotic regions filled with acid-fast bacilli (AFB) in multiple organs. No typical granulomas were identified in the necrotic areas. The amount of AFB within the various organs was significantly higher in the TNFα-knockout mice compared with wild-type mice. TNF messenger RNA can be detected in granulomas in bacillus Calmette-Guérin (BCG)–infected mice (23). Furthermore, injection of anti-TNF IgG antibody significantly reduces the development of granulomas, which are mycobactericidal and play a major role in bacterial containment and elimination. TNFα is involved in host defense against atypical mycobacteria as well. Mice that were genetically deficient in TNFR p55 developed necrotic granulomas when infected with Mycobacterium avium (24). The infection was uniformly fatal in these mice, whereas infected mice with normal TNFR p55 survived for the duration of the study.

In a randomized phase III trial comparing infliximab with placebo treatment in RA patients who were receiving methotrexate, 1 case of TB was reported (5). Seventeen cases of infliximab-associated TB were originally reported from Europe (11 reports) and the US (6 reports), prompting a new TB warning in the infliximab package insert and a recommendation that patients be screened and treated for latent TB prior to treatment with infliximab (1). After drug approval and widespread clinical use of infliximab, 70 cases of TB following infliximab treatment were reported to the FDA as of June 2001 (13) (Table 3). Most of these cases occurred within 12 weeks of the initiation of infliximab therapy. Twelve of these patients died, and at least 4 of the deaths could be attributed to the infection. The authors projected that the background rate of TB in patients with RA was 6.2 cases per 100,000, while the rate of TB among infliximab-treated RA patients in the US was 4-fold greater (24.4 cases per 100,000). Over the next 6 months, 47 additional cases of infliximab-associated TB were reported, increasing the total to 117 cases (25). At that time point, >147,000 patients had been treated with infliximab.

Table 3. Tuberculosis associated with infliximab, a tumor necrosis factor α (TNFα)–neutralizing agent*
  • *

    Except where indicated otherwise, values are the number or the number (%). Adapted, with permission, from ref. 13.

  • Seventeen patients with disseminated disease, 11 with lymph node disease, 4 with peritoneal disease, 2 with pleural disease, and 1 each with paravertebral, meningeal, genital, bladder, enteric, and bone disease.

Tuberculosis cases70
Deaths12 (17) (4 directly related)
Ages, median (range) years57 (18–83)
Weeks of TNF blockade treatment prior to tuberculosis diagnosis, range1–52
Cases of tuberculosis with ≤3 infusions48 (69)
Cases of isolated pulmonary tuberculosis30 (43)
Cases of extrapulmonary tuberculosis40 (57)
Receiving immunosuppressive agents 
Corticosteroids45 (64)
Methotrexate35 (50)
Azathioprine6 (8.6)
Cyclosporine1 (1.4)
History of tuberculosis infection or disease8 (11)
From countries with high incidence of tuberculosis6 (8.6)
From countries with low incidence of tuberculosis64 (91.4)

Several important observations have been made regarding TB in the setting of anti-TNFα therapy, including the following: 1) the incidence of active TB was increased with the use of infliximab; 2) the majority of patients had extrapulmonary TB (57%), in contrast to TB in immunocompetent patients, of whom 18% develop extrapulmonary disease; 3) almost 25% of these patients had disseminated disease, whereas disseminated TB typically accounts for <2% of cases of TB in human immunodeficiency virus (HIV)–negative individuals (26); 4) there were a large number of biopsies used to establish the diagnosis of TB, which may reflect an increase in atypical manifestations of TB in patients receiving TNFα blockade treatment. Granulomas were not observed on histologic specimens in the setting of active disease, consistent with the findings in the knockout mouse models.

In contrast to findings in patients treated with infliximab, in US and European trials of the p75 soluble receptor etanercept (2,024 patients), no cases of TB have been observed (1). However, by 2002, 25 cases of TB in patients receiving etanercept had been reported through the MedWatch reporting system (27). In 13 of these cases (52%) the patients had extrapulmonary disease, and there was 1 death directly related to infection.

Thirteen cases of TB among 2,468 patients receiving adalimumab in the clinical development program for this drug have been reported (28). Seven of these cases of TB occurred early in the clinical trials. Since the majority of those 7 patients had findings consistent with TB on baseline chest radiographs, the FDA recommended TB screening and treatment of TB if present, for all patients prior to study enrollment.

One clinically important distinction between the TNFα inhibitors is that the median time to onset of TB differs markedly. In patients treated with infliximab, the median time is 12 weeks, whereas in those treated with etanercept, it is 46 weeks. The median time to onset of TB in the adalimumab clinical program is 30 weeks. Despite the differences in the number of cases of TB observed with these 3 agents, it should be noted that disseminated TB has been seen with all 3. Currently, there is no clear immunologic explanation for the differences in the incidence of M tuberculosis infection between the various treatments, since they all neutralize TNFα. Pharmacologically, there are important differences. In patients receiving infliximab, the level of TNFα neutralization is sustained for weeks due to slow clearance of IgG from the circulation. The duration of TNFα neutralization is significantly shorter with etanercept. It is possible that the sustained neutralization of TNFα with infliximab or adalimumab may place the patient at greater risk for opportunistic infections such as TB, compared with the risk associated with the more intermittent peaks and troughs of neutralization occurring with etanercept (29).

Streptococcus pneumoniae.

In murine models of pneumococcal pneumonia, mice infected intranasally with S pneumoniae had increased TNFα levels in the lungs and serum, which were proportional to the increased bacterial burden in the lungs (30). The administration of anti-TNFα increased both the microbial burden and mortality. Five of 15 control mice died after infection with S pneumoniae, whereas 11 of 15 anti-TNFα–treated mice died after infection. These results suggest that TNFα helps prevent bacteremia and death. There were significantly fewer circulating neutrophils in the blood on day 7 after infection in the anti-TNFα–treated mice compared with the control group. In another study, anti-TNFα–treated mice had 4-fold more S pneumoniae colony-forming units recovered from the lungs than control mice 40 hours after intranasal inoculation (31). Furthermore, anti-TNFα–treated mice died of pneumococcal pneumonia significantly sooner than control mice. Moreover, in a murine model of pneumococcal peritonitis, 100 colony-forming units of S pneumoniae produced fatal peritonitis in TNFα-deficient mice, but not in wild-type mice (32). TNF deficiency also led to a substantial increase in the level of pneumococci in blood and the spleen.

A case of fatal sepsis and pneumococcal necrotizing fasciitis in a patient receiving etanercept has been reported (2). Another case of fatal pneumococcal sepsis and necrotizing fasciitis in a patient receiving long-term etanercept therapy has occurred at our institution. Pneumococcal necrotizing fasciitis is exceedingly rare in immunocompetent hosts, and its presence suggests a compromised host defense, which in these cases is likely due to TNFα inhibition.

Listeria monocytogenes.

Systemic TNFα release occurs in mice challenged with a lethal dose of L monocytogenes. In mice infected with a sublethal dose of L monocytogenes and then treated with anti-TNF IgG, the sublethal infection is converted to a lethal one (33). Histologic examination of livers and spleens infected with L monocytogenes reveals that control mice exhibit granulomatous inflammation with small numbers of bacteria present, whereas mice treated with anti-TNF IgG have a large bacterial burden, few mononuclear cells, and little granulomatous inflammation. It appears that TNFα plays a role in the formation of granulomas, an important mechanism in limiting growth of intracellular pathogens.

Under normal conditions, immunologic memory follows nonlethal Listeria infection. All control mice administered an immunizing inoculum of Listeria 27 days prior to receiving a lethal dose of Listeria survived the infection. In contrast, mice immunized with Listeria followed by anti-TNF IgG administration died 4 days after challenge. Importantly, administration of exogenous recombinant TNF to mice prior to lethal Listeria challenge prolonged survival times. The livers and spleens of mice administered recombinant TNF prior to Listeria infection had significantly less infection after 24 hours.

As of December 2001, 15 cases of listeriosis in the setting of TNF blockade had been reported to the FDA (34). Fourteen cases were associated with infliximab therapy and 1 with etanercept therapy. The majority of these patients were age 60 years or older and were also receiving at least 1 other immunosuppressive agent. Fever, fatigue, headache, and confusion were the most common symptoms, occurring within 4–290 days of receipt of the first dose of infliximab. Five patients treated with infliximab and 1 treated with etanercept died of Listeria sepsis. In an addendum to that report, the authors noted that since submission of the manuscript, an additional 11 cases of listeriosis had been reported to the FDA, of which 10 were associated with infliximab therapy and 1 with etanercept therapy. Two of the infliximab-treated patients had died of Listeria infection. Two cases of systemic listeriosis associated with infliximab therapy, both occurring in the setting of cholecystitis, leading to meningoencephalitis in 1 case and brain abscess in the other, have also been reported (35).

Aspergillus fumigatus.

In a study in which one group of mice was infected with A fumigatus alone, another given corticosteroids in addition to being infected with Aspergillus, and other groups infected with Aspergillus and given either TNFα or anti-TNFα with or without corticosteroids, no deaths occurred among mice given TNFα, compared with 40–80% mortality in the other groups (36). TNFα-treated mice also had fewer organs infected with Aspergillus. One proposed mechanism to explain the role of TNFα in preventing invasive aspergillosis is through enhanced antifungal activity of polymorphonuclear phagocytes (37). The percentage of polymorphonuclear cell (PMN)–induced hyphal damage was increased 30 minutes after incubation of the PMNs with TNFα. TNFα also increased the production of superoxide anion by PMNs in response to nonopsonized hyphae. Another study, in which both neutropenic and non-neutropenic mice were challenged with intratracheal A fumigatus, demonstrated an increase in lung TNFα levels (38). This was associated with the development of a patchy, peribronchial infiltration with mononuclear cells and PMNs. The administration of antibodies directed against TNFα led to an increase in mortality in both normal and neutropenic mice, in addition to an increase in the fungal burden. There was decreased neutrophil influx in both groups of mice treated with anti-TNFα. The administration of a TNFα agonist peptide to the neutropenic mice 3 days prior to infection with Aspergillus conidia resulted in an increase in the survival rate from 9% to 55%.

The occurrence of invasive aspergillosis in a patient receiving infliximab for Crohn's disease was reported. Of note, it occurred 5 days after administration of the first dose of infliximab, and the patient was not receiving other immunosuppressive therapy (14). Allogeneic bone marrow transplant patients with grade III–IV graft-versus-host disease who received infliximab had a significantly higher risk of invasive aspergillosis (6 of 11 patients) than did patients with similar graft-versus-host disease who did not receive infliximab (4 of 41 patients) (39). The authors of that report recommended that preemptive antifungal therapy directed against filamentous fungi should be strongly considered for this high-risk population.

Histoplasma capsulatum.

Neutralization of TNFα in vivo resulted in increased H capsulatum colony-forming units and 100% mortality in naive and immune mice challenged with H capsulatum administered intranasally (40). H capsulatum may cause subclinical infection or flu-like illness with or without bronchopneumonia in immunocompetent subjects. Patients with marked immunosuppression often present with progressive disseminated histoplasmosis, which is associated with significant mortality. There have been reports of disseminated histoplasmosis following exposure to infliximab (41) and etanercept (42). In the MedWatch voluntary reporting system, 10 patients who developed histoplasmosis were reported, including 9 treated with infliximab and 1 with etanercept (1). In the patients who received infliximab, symptoms of histoplasmosis occurred within 1–24 weeks of the first dose. All of the patients lived in areas endemic for Histoplasma. Nine of 10 patients were treated in intensive care units, and 1 died. Since the publication of the initial FDA report, an additional 12 cases of histoplasmosis associated with anti-TNF therapy have been reported, including 10 in patients treated with infliximab and 2 in patients treated with etanercept (41). Four of these patients died (3 infliximab treated, 1 etanercept treated).

Cryptococcus neoformans.

TNFα has been demonstrated to play a key role in a murine model of pulmonary C neoformans infection. Neutralization of TNFα has prevented pulmonary clearance in mice with pulmonary cryptococcosis (43), possibly through inhibition of cell-mediated immunity. There have been 2 reports of cryptococcal pneumonia in patients with underlying RA who received infliximab therapy, including 1 patient who developed cryptococcal pneumonia after 3 infliximab infusions (44, 45). Several important points regarding TNF blockade can be extrapolated from these case reports. The first is that common illnesses, such as community-acquired pneumonia, may be caused by atypical organisms. Second, in immunocompromised hosts receiving TNF blockade treatment who do not respond to initial empiric antimicrobial therapy, a definitive tissue diagnosis is required. Finally, invasive cryptococcal disease of the lungs can occur despite negative results of tests for serum cryptococcal antigen.

Pneumocystis jiroveci (formerly, Pneumocystis carinii).

TNFα is important in host defense against P jiroveci. Severe combined immunodeficient mice that acquire pulmonary infection with Pneumocystis are able to clear the organism within 19 days after reconstitution with splenic cells from immunocompetent mice. Treatment of reconstituted mice with anti-TNFα IgG almost completely inhibited clearance of Pneumocystis from the lungs (46). The finding of TNFα in lung homogenate supernatants from reconstituted SCID mice further supports the significance of endogenous TNFα in the clearance of pulmonary pneumocystosis. There have been at least 17 cases of Pcarinii pneumonia (PCP) in patients receiving TNFα blockade therapy; however, the majority of these occurred in patients who were receiving other immunosuppressive agents including methotrexate and/or corticosteroids, which could themselves predispose to Pneumocystis pneumonia (1).

Suggestions regarding infectious complications of TNF blockade

Preventive measures.

Tuberculosis.

It is important to note that the following recommendations are not based on controlled clinical trials, and therefore should not replace sound clinical judgment regarding any given patient.

Tuberculin skin testing optimally should be performed prior to initiation of immunosuppressive therapy, since suppression of cell-mediated immunity increases the likelihood of anergy. Although there have been fewer cases of TB following treatment with etanercept compared with infliximab, we recommend tuberculin skin testing in all patients in whom anti-TNFα therapy is considered. The test result should be read at 48–72 hours after inoculation and is considered positive in individuals who have ≥5 mm of induration. Published guidelines have recommended an induration size of ≥5 mm as a threshold for initiating treatment in patients who are at the highest risk of developing active TB (47, 48). This group includes those who have had recent contact with a person with active TB, have been in prison, reside or have traveled in an endemic area, have fibrotic changes seen on chest radiograph, have HIV infection, or have significant immunosuppression (e.g., treatment with ≥15 mg of prednisone per day for ≥4 weeks) (47, 48). Although it is not entirely clear what threshold should be used to define a positive tuberculin skin test result prior to institution of anti-TNFα therapy, there have been cases of active TB in patients with a screening purified protein derivative reaction between 5 mm and 10 mm, suggesting that 5 mm may be the most appropriate cutoff for now. After active TB has been excluded, a minimum of 9 months of daily isoniazid (INH) therapy (300 mg per day [with 50 mg of vitamin B6 per day in patients with a predisposition for peripheral neuropathy]) should be given to patients with evidence of latent TB infection (Table 4).

Table 4. Indications for treatment of latent tuberculosis infection prior to initiation of anti-TNFα therapy*
  • *

    All patients should undergo tuberculin skin testing prior to initiation of anti–tumor necrosis factor α (anti-TNFα) therapy. Chest radiography should be performed in patients with possible active tuberculosis or patients at high risk for latent tuberculosis infection (i.e., those who have had recent contact with a person with active tuberculosis, have recently been in prison, reside or have traveled in an endemic area, have human immunodeficiency virus infection, or otherwise have significant immunosuppression). PPD = purified protein derivative; INH = isoniazid.

All patients with PPD reaction ≥5 mmINH 300 mg daily with supplemental vitamin B6 for 9 months
Patients from areas with high rates of INH-resistant tuberculosisRifampin 600 mg daily for 4 months
Patients exposed to multidrug-resistant tuberculosisPyrazinamide 15 mg/kg/day plus either ethambutol 15 mg/kg/day or fluoroquinolone 500 mg/day for 6–12 months

It is not known how long patients should be treated with INH before it is safe to coadminister anti-TNFα. In the majority of patients with active inflammatory disease, it is probably safe to coadminister the 2 agents, with close observation. In patients who are currently undergoing treatment with anti-TNFα and are exposed to an individual with active TB, INH prophylaxis should be initiated, irrespective of the tuberculin skin test result. Individuals with positive results on tuberculin skin testing who reside in areas where there is significant background resistance to INH should receive treatment with rifampin at 600 mg daily for 4 months. For persons who are likely to be exposed to INH and rifampin (multidrug)–resistant TB and who are at high risk for developing TB, treatment with pyrazinamide and ethambutol or pyrazinamide and a quinolone (i.e., levofloxacin or ofloxacin) for 6–12 months is recommended (48) (Table 4). A recent report proposed that because of the high prevalence of resistance to INH, treatment with a rifampin-containing regimen should be strongly considered for immigrants from Vietnam, Haiti, and the Philippines (49).

In patients who have a history of vaccination with BCG and who undergo tuberculin skin testing prior to initiation of TNF blockade treatment, the tuberculin skin test should be interpreted and treated as if BCG vaccination had not occurred, since BCG skin reactivity wanes over time, and it is difficult to distinguish the effect of BCG from latent TB infection (48).

In persons with latent TB infection, the chest radiographic result is usually normal, although it may show abnormalities suggestive of healed TB. Calcified granulomas pose a lower risk for future progression to active TB, but it is not clear how TNF blockade will affect these lesions. Patients at high risk for TB (as described above) should undergo chest radiography prior to initiation of TNF blockade therapy, in order to potentially increase the yield of latent TB detection. We recommend treatment for latent TB infection, even in the setting of a negative tuberculin skin test result, in patients with radiographic stigmata of prior TB (including calcified granulomas), given the potential risk of reactivation during TNF blockade treatment. Anergy testing (50) lacks standardization and reproducibility, does not predict TB infection, and cannot exclude latent TB infection. It is not recommended in this setting. It is important to recognize that there have been some patients who were appropriately treated for latent TB infection but still developed active TB in the setting of anti-TNFα therapy.

Streptococcus pneumoniae.

The polyvalent capsular polysaccharide pneumococcal vaccine should be administered to patients prior to initiation of anti-TNFα therapy. The optimal time for reimmunization is not known, but reimmunization probably should occur at least every 5 years. A recently approved 7-valent conjugated pneumococcal vaccine has been licensed for use in children and requires further investigation in adults before a formal recommendation can be made. Despite vaccination, a high index of suspicion for the diagnosis of pneumococcal disease in patients treated with TNF inhibition should be maintained, because their response to pneumococcal vaccination may be suboptimal. A recent study examined the effects of anti-TNFα therapies on the immunogenicity of pneumococcal vaccination in 16 patients with rheumatic diseases treated with infliximab or etanercept, 42 patients with RA not treated with infliximab or etanercept, and 20 healthy controls receiving pneumococcal vaccine (51). One month after vaccination, all groups had significant increases in the mean concentration of pneumococcal polysaccharide–specific antibody and in the mean fold increase in levels of antibody to all 7 serotypes, compared with prevaccination levels. However, when individual responses were analyzed according to serotypes, only 12–56% of anti-TNFα–treated patients responded to pneumococcal vaccination, compared with 55–95% of healthy controls.

Patients undergoing TNF blockade treatment should receive pneumococcal vaccination, optimally prior to initiation of anti-TNFα therapy. Questions that remain unanswered include 1) whether revaccination should be administered at the completion of TNF blockade therapy, and 2) whether there is a role for the administration of the 7-valent conjugated pneumococcal vaccine in addition to the 23-valent polysaccharide vaccine.

Pneumocystis jiroveci (formerly, Pneumocystis carinii).

There are insufficient data to recommend Pneumocystis prophylaxis in patients undergoing treatment with TNFα blockade. The decision to administer PCP prophylaxis treatment to these patients should be made on a case-by-case basis taking into account the net state of immunosuppression, which includes the dosages of immunosuppressive agents, the duration of immunosuppression, and the underlying disease process. Pneumocystis prophylaxis should be encouraged in patients who have received ≥15 mg of prednisone daily for ≥4 weeks. Trimethoprim/sulfamethoxazole is the prophylactic treatment of choice in most patients. However, patients who have a severe sulfa allergy may be treated prophylactically with either dapsone, atovaquone, or inhaled pentamidine.

Cryptococcus neoformans.

At this time, there have not been enough reported cases of cryptococcal disease to warrant primary prophylaxis, but secondary prophylaxis with fluconazole 200–400 mg daily should be given to patients undergoing treatment with TNF blockade who have a history of cryptococcal disease. Positive serum or cerebrospinal fluid cryptococcal antigen in the setting of suspected Cryptococcus is diagnostic of active infection and should be treated aggressively, which often includes induction therapy with an amphotericin-based agent followed by maintenance therapy with fluconazole.

Histoplasma capsulatum.

Patients who live in areas with a high prevalence of histoplasmosis should be monitored closely for reactivation of disease while undergoing TNF blockade therapy. Administration of serologic testing and chest radiography prior to immunosuppressive therapy is an unproven strategy to identify patients at risk for Histoplasma reactivation. It should be kept in mind that radiologic evidence of granulomas in these patients may reflect either healed histoplasmosis or healed TB; thus, tuberculin skin testing should be included in the evaluation. Positive urine Histoplasma antigen, unlike findings of serologic testing, indicates active disease and may assist in early diagnosis of disseminated histoplasmosis. There have not been enough reported cases of histoplasmosis in the setting of TNF blockade to warrant routine primary prophylaxis in seropositive individuals. Unresolved issues include whether patients with inflammatory diseases (e.g., RA) who are to receive TNFα blockade treatment and who reside in Histoplasma-endemic areas (seropositive for H capsulatum) should be preferentially given TNF inhibitors with shorter half-lives (e.g., etanercept) rather than agents with longer half-lives (e.g., infliximab and adalimumab).

Coccidioides immitis.

There have been several cases of C immitis infection occurring in patients receiving infliximab therapy (52). Administration of serologic testing and chest radiography prior to immunosuppressive therapy is an unproven strategy to identify patients at risk for coccidioidomycosis reactivation. A positive result on serologic testing for C immitis indicates exposure to the fungus but does not indicate active infection. There have not been enough reported cases of coccidioidomycosis reactivation in the setting of TNF blockade to warrant routine primary prophylaxis in seropositive individuals.

Influenza.

Influenza vaccination should be administered to patients prior to initiation of TNF blockade treatment, to reduce the risk of influenza and, equally as important, to reduce “influenza-like” symptoms that can mimic the prodrome of more serious conditions (e.g., bacteremia, invasive aspergillosis, TB, cryptococcosis).

Empiric treatment.

Rigor.

Since disseminated and necrotizing pneumococcal infections in the setting of TNF blockade have been observed in animal models and described in case reports, one could consider a triage approach in the treatment of patients with rigors as is done with splenectomized patients. A broad-spectrum antibiotic that has potent activity against Pneumococcus (e.g., levofloxacin 500 mg/day) could be supplied to patients receiving TNF blockade therapy, to have readily available if shaking chills occur. This form of therapy is not prophylaxis, but rather early treatment at the first sign of impending bloodstream infection. In areas where there is a high rate of penicillin-resistant and/or cephalosporin-resistant Pneumococcus, it is reasonable to prescribe a fluoroquinolone with excellent pneumococcal activity (e.g., oral levofloxacin 500 mg/day). TNF blockade–treated patients who develop rigors should be directed to take a dose of a broad-spectrum antipneumococcal antibiotic, and to immediately go to a hospital for medical evaluation. Urinalysis, blood and urine culture, and sputum culture (if indicated) should be performed, and treatment with broad-spectrum antibiotics continued. An underlying source should be aggressively pursued with diagnostic imaging. Once a pathogen is identified, the antibiotic coverage can be narrowed to address the specific microbe. Immunosuppressive therapy should be kept to a minimum, and further TNF blockade treatment should be withheld until the infection is eradicated and the patient has improved clinically.

Fever.

Patients with persistent fever (temperature ≥38°C) in the setting of anti-TNF therapy should be evaluated in order to determine the underlying etiology. Cultures should be obtained prior to the initiation of broad-spectrum antibiotic treatment. Aggressive diagnostic imaging should be performed to determine the source of infection. Once a specific pathogen is identified, antibiotic coverage should be narrowed. Immunosuppressive therapy should be minimized, and no further TNF blockade treatment should be administered until the infection has been successfully treated.

Community-acquired pneumonia.

Patients with community-acquired pneumonia should be formally evaluated and treated with antibiotics directed against S pneumoniae and Legionella pneumophila. In cases of community-acquired pneumonia that require hospitalization, sputum and blood cultures should be performed prior to initiation of antibiotic treatment. Initial chest radiography is appropriate to confirm the diagnosis of pneumonia; a chest computed tomography scan should be obtained if the patient's condition does not improve. If sputum cultures, blood cultures, and urine Legionella antigen testing fail to reveal a specific microorganism and the patient is not improving clinically, a biopsy should be performed. Tissue should be sent for both pathologic studies (histopathology, cytology, Gram stain, fungal stain, AFB stain, modified AFB stain, viral stains) and microbiologic studies (Gram stain, aerobic culture, fungal stain, fungal culture, AFB stain and culture, modified AFB stain and culture). Once the diagnosis of the source of the infection is established, antimicrobial treatment can be narrowed.

Conclusion

While therapy with TNF blockade has led to dramatic clinical improvement in certain inflammatory diseases, there has been a price tag associated with its use—typical and atypical infections. Although pulmonary TB and extrapulmonary TB have received the most attention, a wide range of infectious diseases have been observed in the setting of TNF blockade treatment. Since the biologic effects of TNFα on immune cells are widespread, it is not surprising that TNF inhibition has resulted in a decreased ability to control infection, which has been demonstrated in both animal models and human studies. The therapeutic prescription that takes into account the net state of immunosuppression of the patient as well as a rational antimicrobial program is a key component of the management of diseases to be treated with anti-TNF inhibition. As we learn more about infectious diseases associated with TNF blockade, the therapeutic prescription will continue to evolve.

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